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Viral Ubiquitin Ligase Stimulates Selective Host Microrna Expression by Targeting ZEB Transcriptional Repressors

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Viral Ubiquitin Ligase Stimulates Selective Host Microrna Expression by Targeting ZEB Transcriptional Repressors Article Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors Gabriel Lutz 1, Igor Jurak 2,3, Eui Tae Kim 4, Ju Youn Kim 1, Michael Hackenberg 5, Andrew Leader 2,†, Michelle L. Stoller 6, Donna M. Fekete 6, Matthew D. Weitzman 4, Donald M. Coen 2, and Angus C. Wilson 1,* 1 Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; [email protected] (G.L.); [email protected] (J.Y.K.) 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; [email protected] (A.L.); [email protected] (I.J.); [email protected] (D.M.C.) 3 Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia 4 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; [email protected] (E.T.K.); [email protected] (M.D.W.) 5 Department of Genetics, Computational Genomics and Bioinformatics Group, University of Granada, Granada 18071, Spain; [email protected] 6 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; [email protected] (M.L.S.); [email protected] (D.M.F.) * Correspondence: [email protected]; Tel.: +1-212-263-0206. † Current address: Precision Immunology Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA Academic Editor: Thomas Stamminger Received: 10 July 2017; Accepted: 2 August 2017; Published: 7 August 2017 Abstract: Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/δ-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors. Keywords: herpes simplex virus; HSV-1; microRNA; miR-183; miR-96; miR-182; ICP0; E3 ubiquitin ligase; ZEB; host shutoff Viruses 2017, 9, 10; doi:10.3390/v9080210 www.mdpi.com/journal/viruses Viruses 2017, 9, 10 2 of 25 1. Introduction MicroRNAs (miRNAs) function as post-transcriptional regulators of gene expression, limiting protein expression through a combination of mRNA destabilization and translational inhibition [1]. The majority of cellular mRNA transcripts are targeted by at least one, and more often by many, miRNAs creating an integrated network that helps coordinate the output of genes within biological pathways [2]. MiRNAs also contribute to viral pathogenesis, either participating in antiviral defenses or by enhancing viral replication and stabilizing competing programs of viral gene expression [3–6]. Several virus families produce their own viral miRNAs, with the herpesviruses providing the most prominent examples [7]. In the case of the prototype α-herpesvirus, herpes simplex virus 1 (HSV-1, human alphaherpesvirus 1), several viral miRNAs are preferentially expressed in latency, a persistent but largely silent infection restricted to neurons, while others are preferentially expressed during productive (lytic) infection [8–11]. Interestingly, one HSV-1 miRNA, miR-H2, and host miRNA, miR-138, both target a key viral regulatory factor, ICP0, with the host miRNA being a more effective suppressor in both cultured cells and ganglia of infected mice [12–15]. Additional examples of cooperation between viral and host miRNAs to benefit viral replication or latency have been described for other herpesviruses, including human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) [16–18]. In broad strokes, two general strategies have been uncovered by which viruses alter host miRNA–mRNA networks. The first strategy is to express viral miRNAs that mimic existing cellular miRNAs, allowing the virus to exploit an evolutionarily inflexible network of binding sites in target mRNAs. For example, Kaposi’s sarcoma-associated herpesvirus (KSHV), avian Marek’s disease virus-1 and 2 (MDV-1 and MDV-2), EBV, rhesus lymphocryptovirus, and bovine leukemia virus, a retrovirus, encode mimics of miRNAs, miR-155, or miR-29 that promote B-cell tumorigenesis [19–21]. The second strategy is to alter the expression of specific cellular miRNAs. During EBV infection for example, miR-155, is strongly upregulated, allowing the virus to use the pro-oncogenic properties of the host miRNA [17]. Alternatively, some viruses employ various mechanisms to downregulate cellular miRNAs. Herpesvirus saimiri expresses high levels of the H. saimiri U-rich RNAs (HSURs) 1 and 2 non-coding RNAS that hybridize through sequence complementarity to specific target miRNAs and promote their rapid degradation [22]. Additionally, HCMV infection reduces the levels of miR-100, and miR-101, which target components of the mammalian target of rapamycin (mTOR) complex, and delivery of unregulated mimics to replace these miRNAs leads to reduced HCMV replication [23]. Suppression of host gene expression, otherwise known as host shutoff, is especially profound in HSV-1 infections and shapes the viral replication program by sharpening the transitions between different kinetic classes of temporally transcribed mRNAs [24,25]. Mechanisms include deregulation of host gene transcription by RNA polymerase II [26,27], reduced export and processing of host mRNAs [28], accelerated mRNA turnover through the action of viral and host ribonucleases [29,30], and suppression of protein synthesis through alterations to the function and abundance of host factors controlling initiation, elongation, and termination of translation [31]. Because miRNAs are widely used to coordinate the output of gene networks by reducing the stability and translation of multiple mRNAs, they would seem to be logical targets for manipulation by viruses [32], but whether miRNAs are induced or shutoff by HSV-1 infection has remained largely unexplored. Here we show that the levels of three cellular miRNAs, miR-96, miR-182, and miR-183, but not most others, are substantially increased during HSV-1 infection of primary cells. As induction of host mRNAs (and miRNAs) by HSV-1 is infrequent, we investigated further and found that this increase is mediated by the viral immediate-early protein ICP0 through its E3 ubiquitin ligase function and reflects transcriptional activation of a single chromosomal locus encoding all three miRNAs. ICP0 regulates a variety of cellular processes, in part by targeting cellular regulatory factors for degradation by the proteasome. As shown here, these targets include ZEB1 and ZEB2, host transcription factors that suppress the transcription of genes involved in maintaining differentiated cell states, including the miR-183/96/182 locus [33,34]. Viruses 2017, 9, 10 3 of 25 2. Materials and Methods 2.1. Viruses The following HSV-1 strains were used: wild type HSV-1 GFP-Us11 (strain Patton) [35] and wild type HSV-1 (strain KOS), 7134 (∆ICP0) and 7134R (ICP0-rescue) viruses originally from Dr. Pricilla Schaffer (Harvard Medical School, MA, USA) [36], HSV-1 n12 (∆ICP4) virus from Dr. Neal DeLuca (University of Pittsburgh School of Medicine, PA, USA) [37], HSV-1 d27-1 (∆ICP27) virus from Dr. David Knipe (Harvard Medical School, MA, USA) [38], and HSV-1 HP66 (∆DNA polymerase) [39]. Recombinant adenoviruses (gifts from Drs. William Halford and Pricilla Schaffer [40]) were as follows: Ad.T-n212 (Ad-ΔICP0), Ad.T-ICP4, Ad.T-ICP0, Ad.T-VP16, and Ad.C-rtTA. For adenoviral delivery of the miR-183 cluster, a bifunctional cassette containing the miR-183 family and green fluorescent protein (GFP) [41], was shuffled into the adenoviral vector AD5-CMV-V5-DEST (Invitrogen, Carlsbad, CA, USA) using Gateway® LR Clonase (Invitrogen). Stocks of the wild type KOS and GFP-Us11 viruses were amplified in Vero cells (American Type Culture Collection (ATCC), Manassas, VA, USA) infected for 1 h at 37 °C at a multiplicity of infection (MOI) of 0.01 in Dulbecco's Modified Eagle's medium (DMEM, Invitrogen) supplemented with 2% fetal bovine serum (FBS, Gibco Laboratories, Gaithersburg, MD, USA) and 1% penicillin/streptomycin/L-glutamine (Invitrogen) (v/v). Infected cultures were incubated at 37 °C in fresh media until cytopathic effects were observed in all cells and then frozen at −80 °C. Virus was liberated by three freeze/thaw cycles with or without sonication and titers determined by plaque assay on Vero cell monolayers. All adenoviruses were propagated in 293A cells cultured in 15 cm dishes and the titer determined by plaque assay in 293A cells (ATCC). 2.2. Cell Lines and Infections 293A and 293T cells (both from ATCC) were routinely cultured in DMEM containing 10% FBS and 1% penicillin/streptomycin/L-glutamine (Invitrogen) (v/v), while Vero cells were cultured in similar media but containing 5% bovine calf serum (BCS). Rat embryonic fibroblast cultures (REFs) were prepared from E18 Sprague Dawley® rat pups (Charles River Laboratories, Kingston, NY, USA) after decapitation and removal of the internal organs.
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